Role of kinins in mediating vascular function in healthy pregnancy and pre-eclampsia

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Abstract

Pre-eclampsia is a pregnancy-related disorder characterised by high blood pressure,
proteinuria and oedema. The aetiology of the disease is unclear but evidence suggests
that endothelial dysfunction is central to the development of the maternal syndrome.
Kinins are endogenous peptides released by the endothelium that contribute to the
regulation of cardiovascular homeostasis by inducing vasodilation, fibrinolysis and
angiogenesis. Given that pre-eclampsia is associated with reduced endotheliumdependent
relaxation, coagulation abnormalities and an angiogenic imbalance, it was
hypothesised that alterations of kinin receptor-mediated responses may be involved in
the pathogenesis of the condition.
To investigate whether changes in kinin receptor activity are involved in the impairment
of endothelium-dependent relaxation observed in pre-eclampsia, the effects of specific
B2 and B1 receptor agonists and antagonists on myometrial vascular tone were tested on
arteries from healthy pregnancy and pre-eclampsia. The results demonstrated that in
addition to classical bradykinin B2 receptor-mediated relaxation, a subset of healthy
patients exhibited nitric oxide-dependent relaxation to the B1 receptor agonist Lys-des-
Arg9-BK (LDABK) which could not be inhibited by either B1 or B2 receptor antagonists.
Also, vessels that exhibited this novel response to LDABK were more sensitive to
bradykinin. Furthermore, this study revealed that patients with pre-eclampsia had an
attenuated response to both bradykinin and LDABK. Immunolocalisation and mRNA
expression of the kinin receptors in the myometrium revealed no differences between
healthy pregnancy and pre-eclampsia suggesting that disturbances of kinin receptor
signalling rather than changes in receptor distribution or expression levels may be
involved in the reduction of kinin-mediated responses in these patients.
The role of kinins in mediating placental angiogenesis in healthy pregnancy and preeclampsia
was determined using the endothelial tube formation assay in primary human
umbilical vein endothelial cells (HUVECs) isolated from healthy women and women with pre-eclampsia. B2 and B1 receptor agonists induced endothelial tube formation via a
VEGF-dependent, nitric oxide-independent mechanism in healthy HUVECs cultured in
normoxic conditions. HUVECs isolated from women with pre-eclampsia cultured under
normoxia and HUVECs from healthy pregnancies cultured under hypoxia exhibited
greater levels of angiogenic branching compared with healthy normoxic cells, but were
unresponsive to bradykinin and LDABK. Incubation of these cells with a VEGF
receptor inhibitor reduced the elevated levels of tube formation indicating that this effect
may be due to hypoxic upregulation of VEGF or an intrinsic difference in their
angiogenic capacity. Further studies are required to determine the cause for the
differences in angiogenic potential between healthy and pre-eclamptic cells and the
impact this could have on placental vascular development and the pathogenesis of preeclampsia.